# Discovery of long-acting, chemoprotective antimalarial compounds

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $712,608

## Abstract

ABSTRACT
To discover leads for next-generation chemoprotective antimalarial drugs, we tested >500,000 compounds
for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium parasites (681 with
an IC50 < 1 µM). Cluster analysis identified potent and previously unreported scaffold families as well as
other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic
assays that predict stage-specific and multispecies antimalarial activity revealed compound classes that
are likely to provide symptomatic relief from blood-stage and others that only prevent malaria. Target
identification using functional assays, in vitro evolution or metabolic profiling of the most potent blood
stage-active scaffolds revealed multiple mitochondrial inhibitors but also compounds with likely new
mechanisms of action. The total dataset provided hundreds of new chemotypes and scaffold families
(compounds sharing a core structure) that may be used in further drug development for the treatment and
prevention of malaria. Here we propose to perform hit to lead optimization on 1-2 scaffold families per
year, synthesizing approximately ~750 compounds. Select compounds (10%) will be tested for
microsomal stability, protein binding, hERG, and CYP inhibition. Pharmacokinetic and prophylactic animal
model testing will be performed on ~10 compounds per year. In addition, we will explore whether promising
leads can be converted to a prodrug form that can be given as intramuscular injection which provides long-
lasting chemoprevention. Hit to lead optimization will be accompanied by investigation into the mechanism
of action of six scaffold families using a suite of different methods including in vitro evolution and whole
genome analysis. We aim to develop treatments that may prevent malaria from developing, that are
convenient to use and which are superior to current medicines.
.

## Key facts

- **NIH application ID:** 10132240
- **Project number:** 5R01AI152533-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Elizabeth A Winzeler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $712,608
- **Award type:** 5
- **Project period:** 2020-03-25 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132240

## Citation

> US National Institutes of Health, RePORTER application 10132240, Discovery of long-acting, chemoprotective antimalarial compounds (5R01AI152533-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132240. Licensed CC0.

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